EP0884327B1 - Dendritische, lysinhaltige Polypeptide zur gezielten Arzneimittelabreichung - Google Patents

Dendritische, lysinhaltige Polypeptide zur gezielten Arzneimittelabreichung Download PDF

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EP0884327B1
EP0884327B1 EP97304060A EP97304060A EP0884327B1 EP 0884327 B1 EP0884327 B1 EP 0884327B1 EP 97304060 A EP97304060 A EP 97304060A EP 97304060 A EP97304060 A EP 97304060A EP 0884327 B1 EP0884327 B1 EP 0884327B1
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group
groups
reagent
focal
amine
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EP0884327A1 (de
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Alexander T. c/o The School of Pharmacy Florence
Thiagarajan The School of Pharmacy Sakthivel
Andrew F. The School of Pharmacy Wilderspin
Istvan The School Of Pharmacy Toth
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School of Pharmacy University of London
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Priority to US09/096,411 priority patent/US6194543B1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/642—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to polypeptide compounds which have dendritically linked units formed from amino acids having reactive groups, for instance carboxylic acid or amine groups, in their side chains.
  • Each molecule comprises two dendrons.
  • anchor groups each of which comprises at least one lipophilic group.
  • the terminal units of the at least one other dendron may be unconjugated or may be conjugated to ligons of various types.
  • the dendrons are attached at a core which may include a linear oligo peptide, optionally having pendant sugar molecules.
  • Tam et al, in Proc.Nat.Acad.Sci.USA(1988) 85, 5409-5413 describe a compound including a dendritically linked polylysine component, to the focal lysine of which is attached a lipophilic moiety, through a peptide bond to the carboxylic acid group of that lysine unit.
  • a dendritically linked polylysine component to the focal lysine of which is attached a lipophilic moiety, through a peptide bond to the carboxylic acid group of that lysine unit.
  • To the terminal branches of the dendritic moiety there may be attached peptide antigens to provide an active ingredient for a vaccine having improved antigenicity.
  • WO-A-95/00540 describes dendritic carriers, in which the dendrons include lysine or other di-amino carboxylic acids.
  • the carrier may include a hydrophobic group connected by a linker to the focal group of the dendritic molecule.
  • the hydrophobic group is linked following cleavage of the dendrimer from the carrier. Suitable hydrophobic groups are derived from fatty acids or fatty alcohols.
  • Toth et al describe an improvement of Tam's invention, in which the anchor component is formed from lipophilic amino acids.
  • the anchor component is formed from lipophilic amino acids.
  • This allows the compound to be synthesised using conventional solid state peptide synthetic techniques, in the first stages of which the lipophilic amino acids are linked to form, for instance, a three unit linear oligo peptide, a focal lysine unit is joined to the final lipophilic amino acid and the dendritic core moiety is then linked to the two amine groups of the focal lysine unit.
  • the peptide antigens may subsequently be synthesised directly onto the terminal branches of the dendritic core, all the steps being carried out without cleavage of the polypeptide from the solid substrate carrier.
  • Toth et al's product required the use of starting amino acid reagents with the same protecting group blocking the two amine groups of lysine reagents. Consequently during the steps in which the dendritic component is synthesised, the same reagent is added to each of the amine moieties.
  • the dendritic polylysine and the peptide antigen can be synthesised using solid state peptide synthetic methods
  • the polylysine-polyantigen compound must be cleaved from the carrier substrate prior to conjugation to the lipophilic anchor moiety, through the carboxylic acid unit of the focal lysine group.
  • the reagent, from which Tam's lipophilic anchor is synthesised, has only one reactive group.
  • a new dendritic compound according to the present invention comprises a core including a focal group from which at least two dendrons extend, each dendron comprising dendritically linked amino acid units I in which R 1 is C 1-6 -alkylene and X is selected from the group consisting of -O-, -S-, -NH- and -CO-, and each unit of a dendron may have the same groups R 1 and X, and in which a first dendron had n (where n is 2) levels of dendritically linked amino acid units and 2 n terminal branches, to p (where p is at least 2) of which terminal branches there are linked anchor groups where Y is selected from -CO-, -NH-, -O- and -S-, provided that at least one of X and Y is -CO-,
  • the focal group of the core is linked through covalent bond to the at least 2 dendrons.
  • the core may include components other than the focal unit, for instance joined to the focal unit by one or more additional covalent bond.
  • the focal group is an amino acid unit, for instance having the formula I in which X and R 1 are as defined above.
  • X is either -NH- or -CO-. Where it is -CO-, the two dendrons are attached to the two -CO- moieties. Where X is NH, the two dendrons are linked one each to the groups NH.
  • the focal group is formed from lysine or ornithine.
  • the core may comprise units other than the focal group. Such units are preferably peptide linked amino acid based units. Additional core units may function merely as spacers, or may include functional groups such as lipophilic groups, hydrophilic groups or active ligands, for instance targeting groups.
  • the compound may be attached to a resin through the focal unit, for instance via a spacer.
  • the present invention is made possible by the use in the synthesis of the dendritic compound of a reagent for forming the focal group which has at least three reactive groups, each of which can be sequentially reacted.
  • the focal group is an amino acid unit of the formula I where the group X is -NH-
  • the reagent from which the focal unit is derived has the two amine groups protected by two different protecting groups which are removable under different conditions. Each amine group can consequently be protected, activated and reacted in sequential series of reaction steps. This allows two different dendrons to be synthesised.
  • the present invention includes also a method for synthesising the novel compound in which a focal reagent which has two reactive groups is reacted in a first series of first dendron producing steps as follows:
  • a focal reagent of the formula VI in which R 17 , R 18 and R 19 are selected from the same groups as R 14 , R 16 and R 15 , respectively, as defined above, with a substrate having a pendant group which is capable of reacting with one of the groups XR 17 , -NHR 18 and -COR 19 , optionally after deprotection and/or activation of the said pendant group or said one of the groups of the focal reagent, whereby the focal reagent is bound to the substrate.
  • the series of reactions used to form the dendron having lipophilic moieties R 2 may be carried out before or after the series of reactions to form the other dendron.
  • the reference to the first series of steps and second series of steps does not, unless the context makes it explicit, imply an order of carrying out the said series.
  • R 2 is preferably selected from C 6-24 -alkyl, - alkenyl or - alkynyl, or is a group IV in which R 4 is a bond or a C 1-6 -alkylene group,
  • the compound is derived from a lipidic amino acid of the formula V wherein R 6 is as defined above.
  • a lipidic amino acid is conjugated to the terminal branches of the first dendron whichever of the COOH and NH 2 group is not desired to react with the terminal branch is generally blocked by an appropriate protecting group.
  • a monofunctional reagent to provide the anchor moieties for instance a fatty acid or fatty amine.
  • the dendritic compound of the invention may be bound to a solid support, for instance a resin used as the solid peptide synthesis support.
  • a solid support for instance a resin used as the solid peptide synthesis support.
  • the core is joined to the solid support, for instance a resin, through the focal unit, optionally via a spacer, for instance an oligopeptide spacer.
  • the compound may be cleaved from the support prior to use, optionally after having reacted further any of the underivatised terminal branches.
  • the unreacted terminal branches may be in the form of free or protected carboxylic acid, amine, hydroxyl or thiol groups.
  • the dendritic compound has several terminal primary amino groups or is in the form of the corresponding ammonium salt. Usually all the terminal groups of the second dendron are amine or ammonium groups.
  • At least some of the terminal groups of the second dendron are attached to an organic group comprising a sugar molecule.
  • all of the terminal branches of the first dendron to be provided with lipophilic anchor moieties. It is found that two or four such moieties are adequate to provide appropriate levels of lipophilicity to the compound as a whole.
  • the second dendron has at least three levels of dendritically linked amino acid units, preferably four or, sometimes five levels of dendritically linked amino acid units (that is, m is 3 to 5). Where there are five or more levels of dendritically linked amino acid units, stearic hindrance may prevent full dendritic linkage of groups, for instance further dendritic moieties, to the terminal units. Consequently it is preferred for there to be no more than five, and preferably four, levels of dendritically linked amino acid units.
  • the dendrimer of the present invention having four anchor groups being lipidic amino acid units joined to the amine terminal groups of the first dendron, and with free amino groups at each of the terminal groups of 3-, 4- and 5- level dendritically linked amino acid units for the second dendron have reduced toxicity as determined by erythrocyte lysis, as compared to a lipid peptide dendromer as described in our earlier application WO-A-94/02506 comprising a linear oligopeptide anchor moiety of three lipidic amino acids joined to the focal lysine of a dendrimer having the equivalent number of levels of dendritically linked amino acid (lysine) units.
  • the compound of the invention has a similar utility to those described in WO-A-94/02506.
  • conjugated peptide antigens for instance antibodies or sugar groups, or other groups providing increased levels of hydrophilicity (for instance sugar molecules, polyethylene glycol molecules or ionic moieties).
  • Polystyrene aminomethylated (PAM) resin BOC-protected aminoacids from Novabiochem, 2-(1H benzotriazole-lyl)-1,3,3,-tetramethyluronium hexafluorophosphate (HBTU) from Phase Separations Ltd, Trifluoroacetic acid (RFA) from Halocarbon Products Corporation, hydrogen fluoride gas (HF) from BOC, diisopropyl ethyl amine (DIEA) from Fluka and dimethylformaamide (DMF) from Rathburn were all used as received.
  • the protected lipidic aminoacids were synthesised and purified in our laboratory as described in Gibbons, WA, et al (1990) Liebigs Ann.Chem. 1177-1183.
  • Solid phase peptide synthetic methods were used employing a polyacrylamide resin having a degree of substitution of 0.46 mmol/g resin.
  • the reaction sequence is shown in slow diagram Figure 1 the step involving protection of Boc was performed in 100% trifluoroacetic acid. Couplings of pendant amine groups on the bound compound with carboxylic acid groups of amino acid reagents having protected amine groups was achieved using a three fold excess of HBTU activated Boc-amino acids in dimethylformamide in the presence of diisopropylethyl amine. Acidulation of deprotected Boc group of lipoamino acid was carried out in the presence of diisopropylethyl amine. Deprotection of the Fmoc group to form the second dendron was carried out by a suitable system.
  • the resin peptide was carefully flow washed before and after each deprotection step. The final product was washed with dichloromethane and dried in air. The peptide was removed from the resin support with a high HF method 2 g resin peptide, 20 ml HF, 1.5 hour at -5°C) to yield the crude peptide which was dissolved in 95% acetic acid solution and lyophilised.
  • Analytical HPLC separation of the synthesised dendrimers was carried out on a 25 cm Vydac C 18 RAC column with 5 ⁇ m pore size and 4.6 mm internal diameter. Following standard degassing techniques, particulate matter was removed from HPLC grade acetonitrile and water using membrane filters. Analytical separation was achieved with a solvent gradient beginning with 0% acetonitrile, increasing to 60% acetonitrile at 20 min. maintaining at this concentration for 20 min and decreasing steadily to 0% acetonitrile for 10 min at a constant flow of 1.2 ml min -1 . For preparative separation a TSK-GEL preparative C 18 column with 10 ⁇ m pore size and 2.5 cm internal diameter was used.
  • the compounds synthesised have the values for the number of lipid residues and the number of primary amine groups as well as the molecular weight shown in Table 1.
  • Compound R Levels of dendritically linked lys residues in 2nd dendron No 1° amine groups MW 1.1 NH 2 3 8 2500 1.2 Lys(NH 2 ) 2 4 16 3526 1.3 Lys(Lys(NH 2 ) 2 ) 2 5 32 5577
  • the methylol compound was synthesised by subjecting the compound having eight free amine groups at the terminal ends to reaction with a suitable reagent.
  • the compounds synthesised are shown in Table 2 below.
  • PBS chilled phosphate buffered saline
  • the toxicity of compounds 1.1-1.7 were compared with linear polylysine of two different molecular weights (34,000 and 1000-4000). Triton X100 was used as positive control.
  • the higher M.W. polylysine had a concentration independent toxicity 35.7% to 54.2% of percent population lysis was observed between the concentrations 1 ⁇ g/ml to 30 ⁇ g/ml.
  • the lower M.W. polylysine was found to be almost nontoxic.

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Claims (20)

  1. Dendritische Verbindung, umfassend einen Kern, der eine fokale Gruppe einschließt, von der mindestens zwei Dendrons ausgehen, wobei jedes Dendron dendritisch verknüpfte Aminosäureeinheiten I
    Figure 00210001
    umfaßt, worin R1 C1-6-Alkylen ist und X aus der Gruppe, bestehend aus -O-, -S-, -NH- und -CO-, ausgewählt ist und jede Einheit eines Dendrons die gleichen Gruppen R1 und X aufweisen kann, und worin ein erstes Dendron n (wobei n 2 ist) Ebenen von dendritisch verknüpften Aminosäureeinheiten und 2n endständige Zweige aufweist, wobei mit p (wobei p mindestens 2 ist) endständigen Zweigen Ankergruppen
    Figure 00210002
    verknüpft sind, worin Y aus -CO-, -NH-, -O- und -S- ausgewählt ist, mit der Maßgabe, daß mindestens eines von X und Y -CO- ist,
    R2 eine organische Gruppe ist, die mindestens eine C6-24-Alkyl-, -Alkenyl- oder -Alkinylgruppe enthält,
    R3 aus der Gruppe, bestehend aus Wasserstoff, Amin, blockiertem Amin, Hydroxyl, C1-24-Alkoxy, Thiol, COOH oder einer organischen Gruppe, die mindestens eine C6-24-Alkyl, -Alkenyl oder -Alkinylgruppe, C1-6-Alkanoyloxy oder C1-6-Alkanamido enthält, ausgewählt ist,
       und worin ein zweites Dendron m (wobei m im Bereich von 3 bis 5 liegt) Ebenen von dendritisch verknüpften Aminosäureeinheiten der Formel I oben, worin die Gruppen R1 und X gleich oder verschieden voneinander und gleich denjenigen der Aminosäureeinheiten im ersten Dendron oder davon verschieden sein können, und 2m endständige Zweige aufweist, von denen ein jeder entweder unkonjugiert ist und eine Gruppe darstellt, die aus NH2, N+H2R11, worin R11 Wasserstoff oder C1-4-Alkyl, COOH, COO-, OH oder SH ist, ausgewählt ist, oder über die endständige -X-, -NH- oder -CO-Gruppe mit einer Gruppe R12 konjugiert ist, wobei R12 eine Methylolgruppe, ein aktiver Ligand oder eine organische Gruppe ist, die eine Zuckergruppe umfaßt.
  2. Verbindung nach Anspruch 1, worin die fokale Gruppe eine Aminosäureeinheit der Formel I
    Figure 00220001
    ist, worin X und R1 wie oben definiert sind.
  3. Verbindung nach Anspruch 2, worin X in der fokalen Gruppe -CO- oder -NH- ist.
  4. Verbindung nach Anspruch 3, worin X in der fokalen Gruppe -NH- ist.
  5. Verbindung nach Anspruch 4, worin die fokale Gruppe von Lysin oder Omithin gebildet wird, d.h., R1 ist -(CH2)4- oder -(CH2)3-.
  6. Verbindung nach irgendeinem der vorhergehenden Ansprüche, worin 2n = p ist.
  7. Verbindung nach irgendeinem der vorhergehenden Ansprüche, worin jeder endständige Zweig des zweiten Dendrons -NH2 oder -N+H2R11 ist.
  8. Verbindung nach irgendeinem der vorhergehenden Ansprüche, worin die Gruppen R1 und X in jeder der Gruppen der Formel I gleich sind.
  9. Verbindung nach Anspruch 8, worin X -NH- ist und R1 -(CH2)4- oder -(CH2)3- ist.
  10. Verbindung nach irgendeinem der vorhergehenden Ansprüche, welche über die fokale Einheit des Kerns an einen Harzträger gebunden ist.
  11. Verbindung nach Anspruch 10, welche über einen Spacer an den Träger gebunden ist.
  12. Zusammensetzung, umfassend eine Verbindung nach irgendeinem der vorhergehenden Ansprüche.
  13. Pharmazeutische Zusammensetzung, umfassend einen pharmazeutischen Exzipienten und eine Verbindung nach irgendeinem der Ansprüche 1 bis 9.
  14. Syntheseverfahren, worin ein fokales Reagenz, welches zwei reaktive Gruppen aufweist, umgesetzt wird in einer ersten Folge von Schritten zur Bildung eines ersten Dendrons wie folgt:
    1. ein Aminosäurereagenz der Formel II
    Figure 00230001
    worin R1 und X wie in Anspruch 1 definiert sind,
    R14 H ist, wenn X -O-, -S- oder -NH- ist,
    OH ist, wenn X -CO- ist, oder eine Schutzgruppe ist,
    R15 eine Carbonsäure-Schutzgruppe, Hydroxyl oder eine Carbonsäure-aktivierende Gruppe ist,
    R16 H, eine Amin-Schutzgruppe oder eine Amin-aktivierende Gruppe ist, vorausgesetzt, daß mindestens zwei von R14, R15 und R16 keine aktivierende Gruppe sind und mindestens eines von R14, R15 und R16 keine Schutzgruppe ist,
    wird mit dem fokalen Reagenz umgesetzt, gegebenenfalls nach einem Schritt, in dem die gewünschte reaktive Gruppe des fokalen Reagenz von der Schutzgruppe befreit und/oder aktiviert wird, wodurch die reaktive Gruppe auf dem fokalen Reagenz mit einer der Gruppen R14X-, R15CO- und R16NH- reagiert;
    2. ein zweiter Schritt, in dem beide nicht umgesetzten Gruppen R14X-, R15CO- und R16NH- des Produkts des vorhergehenden Schritts erforderlichenfalls von der Schutzgruppe befreit und/oder aktiviert werden und mit mindestens zwei Äquivalenten eines trifunktionellen Reagenz der allgemeinen Formel II
    Figure 00240001
    umgesetzt werden, worin die Gruppen R1, R14, R15 und R16 wie in Schritt 1 definiert sind und die gleichen wie in dem in Schritt 1 eingesetzten trifunktionellen Reagenz oder davon verschieden sind;
    3. eine Wiederholung von Schritt 2, wobei mindestens vier Äquivalente des trifunktionellen Reagenz der allgemeinen Formel II eingesetzt werden; und
    4. ein Ankergruppen-Verknüpfungsschritt, worin mindestens zwei der vier Gruppen R14X-, R15CO- und R16NH- erforderlichenfalls von der Schutzgruppe befreit und/oder aktiviert werden und mit einem lipophilen Reagenz der Formel III
    Figure 00240002
    umgesetzt werden,
    worin Y, R2 und R3 wie oben definiert sind und R17 OH oder eine Carbonsäure-aktivierende Gruppe ist, wenn Y -CO- ist,
    oder R17 H oder eine Amin-, Hydroxyl- oder Thiol-aktivierende Gruppe ist, wenn Y -NH-, -O- oder -S- ist,
    wodurch die genannten mindestens zwei Gruppen mit R17Y- reagieren, um
    Figure 00240003
    mit dem X, CO- oder NH- zu konjugieren;
    und einer Folge von Reaktionsschritten zur Bildung eines zweiten Dendrons, beinhaltend
    1. daß die andere der reaktiven Gruppen des fokalen Reagenz in einem Schritt, welcher von Schritt 1 der ersten Folge von Schritten zur Bildung des ersten Dendrons getrennt ist, mit einem Aminosäurereagenz der Formel II
    Figure 00250001
    umgesetzt wird, worin R1 und X wie oben definiert sind,
    R14 H ist, wenn X -O-, -S- oder -NH- ist,
    OH ist, wenn X -CO- ist, oder eine Schutzgruppe ist,
    R15 eine Carbonsäure-Schutzgruppe, Hydroxyl oder eine Carbonsäure-aktivierende Gruppe ist,
    R16 H, eine Amin-Schutzgruppe oder eine Amin-aktivierende Gruppe ist,
    vorausgesetzt, daß mindestens zwei von R14, R15 und R16 keine Aktivierungsgruppe sind und mindestens eines von R14, R15 und R16 keine Schutzgruppe ist;
    gegebenenfalls nach einem Schritt, in dem die gewünschte reaktive Gruppe des fokalen Reagenz und/oder eine der Gruppen -XR14, -COR15
    und -NHR16 von der Schutzgruppe befreit und/oder aktiviert wird, wodurch die andere der reaktiven Gruppen auf dem fokalen Reagenz mit einer der Gruppen R14 X-, R15CO- und R16NH- reagiert;
    2. einen zweiten Schritt, in dem beide nicht umgesetzten Gruppen R14X-, R15CO- und R16NH- des Produkts des vorhergehenden Schritts erforderlichenfalls von der Schutzgruppe befreit und/oder aktiviert werden und mit mindestens zwei Äquivalenten eines trifunktionellen Reagenz der allgemeinen Formel II
    Figure 00250002
    umgesetzt werden, worin die Gruppen R1, R14, R15 und R16 wie in Schritt 1 definiert sind und die gleichen wie in dem bei Schritt 1 eingesetzten trifunktionellen Reagenz oder davon verschieden sind;
    3. (m-1) Wiederholungen von Schritt 2, wobei in jedem Fall mindestens 2(r+1) Äquivalente des trifunktionellen Reagenz für die r. Wieder-holung des Schritts 2 eingesetzt werden, bis m Ebenen von dendritisch verknüpften Aminosäuren gebildet wurden, wobei m im Bereich von 3 bis 5 liegt.
  15. Verfahren nach Anspruch 14, beinhaltend einen einleitenden Schritt der Umsetzung eines fokalen Reagenz der Formel VI
    Figure 00260001
    worin R17, R18 und R19 aus den gleichen Gruppen wie R14, R16 bzw. R15 wie in Anspruch 14 definiert ausgewählt sind, mit einem Substrat, das eine Seitengruppe aufweist, welche zur Reaktion mit einer der Gruppen -XR17, -NHR18 und -COR19 in der Lage ist, gegebenenfalls nach Befreiung von der Schutzgruppe und/oder Aktivierung der Seitengruppe, wodurch das fokale Reagenz an das Substrat gebunden wird.
  16. Verfahren nach Anspruch 15, worin das Substrat ein immobiler Träger, vorzugsweise ein Harz, noch bevorzugter ein Harz auf Polyacrylamidbasis, ist.
  17. Verfahren nach Anspruch 16, worin das Harz seitenständige Amingruppen aufweist und worin die Gruppe -COR19 mit diesen seitenständigen Amingruppen in Gegenwart einer aktivierenden Verbindung umgesetzt wird, um eine Peptidbindung zu bilden.
  18. Verfahren nach Anspruch 17, worin R17 und R18 jeweils unterschiedliche Amin-Schutzgruppen sind.
  19. Verfahren nach irgendeinem der Ansprüche 14 bis 18, worin in jedem der Schritte in einer der jeweiligen Folgen das Reagenz der Formel II gleich ist, vorzugsweise, worin das Reagenz der Formel II für jede Folge das gleiche ist.
  20. Verfahren nach Anspruch 19, worin X -NH- ist und worin die Gruppen R14 und R15 die gleichen Amino-Schutzgruppen sind.
EP97304060A 1997-06-11 1997-06-11 Dendritische, lysinhaltige Polypeptide zur gezielten Arzneimittelabreichung Expired - Lifetime EP0884327B1 (de)

Priority Applications (4)

Application Number Priority Date Filing Date Title
DE69704269T DE69704269T2 (de) 1997-06-11 1997-06-11 Dendritische, lysinhaltige Polypeptide zur gezielten Arzneimittelabreichung
EP97304060A EP0884327B1 (de) 1997-06-11 1997-06-11 Dendritische, lysinhaltige Polypeptide zur gezielten Arzneimittelabreichung
US09/096,411 US6194543B1 (en) 1997-06-11 1998-06-11 Dendritic polypeptides
JP10202681A JPH11124396A (ja) 1997-06-11 1998-06-11 樹状ポリペプチド

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Application Number Priority Date Filing Date Title
EP97304060A EP0884327B1 (de) 1997-06-11 1997-06-11 Dendritische, lysinhaltige Polypeptide zur gezielten Arzneimittelabreichung

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EP0884327A1 EP0884327A1 (de) 1998-12-16
EP0884327B1 true EP0884327B1 (de) 2001-03-14

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US (1) US6194543B1 (de)
EP (1) EP0884327B1 (de)
JP (1) JPH11124396A (de)
DE (1) DE69704269T2 (de)

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US6906182B2 (en) 2000-12-01 2005-06-14 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and method of use
WO2008017125A1 (en) * 2006-08-11 2008-02-14 Starpharma Pty Ltd Targeted polylysine dendrimer therapeutic agent
US9127130B2 (en) 2006-08-11 2015-09-08 Starpharma Pty Ltd. Polylysine dendrimer contrast agent

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ATE311202T1 (de) 1998-09-23 2005-12-15 Univ London Pharmacy Kationische dendrimer verbindungen und deren verwendung als oligonucleotid/polynucleotid träger
GB9912911D0 (en) 1999-06-04 1999-08-04 Zeneca Ltd Chemical process
US6774102B1 (en) * 1999-09-29 2004-08-10 Gambro Dialysatoren Gmbh & Co. Kg Extracorporeal endotoxin removal method
US7314956B2 (en) 2001-08-08 2008-01-01 Vaxim, Inc. Multifunctional carrier for the delivery of a pharmacological agent or genetic material into a cell
KR20080031421A (ko) * 2005-07-18 2008-04-08 더 스크립스 리서치 인스티튜트 양쪽성 덴드리머의 제조방법
US9603941B2 (en) * 2006-01-24 2017-03-28 Minghui Chai Method of preparing dendritic drugs
US20110150837A1 (en) * 2009-12-23 2011-06-23 Flamel Technologies Amphiphilic polymer functionalized by methionine
CN102936337B (zh) * 2012-10-30 2014-10-22 中国科学院长春应用化学研究所 聚(γ-炔丙基-L-谷氨酸酯)-聚氨基酸嵌段共聚物、功能化嵌段共聚物及制备方法

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US6906182B2 (en) 2000-12-01 2005-06-14 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and method of use
US7262177B2 (en) 2000-12-01 2007-08-28 Cell Works Therapeutics, Inc. Conjugates of glycosylated/galactosylated peptide, bifunctional linker, and nucleotidic monomers/polymers, and related compositions and methods of use
WO2008017125A1 (en) * 2006-08-11 2008-02-14 Starpharma Pty Ltd Targeted polylysine dendrimer therapeutic agent
US8420067B2 (en) 2006-08-11 2013-04-16 Starpharma Pty Ltd Targeted polylysine dendrimer therapeutic agent
US9127130B2 (en) 2006-08-11 2015-09-08 Starpharma Pty Ltd. Polylysine dendrimer contrast agent

Also Published As

Publication number Publication date
JPH11124396A (ja) 1999-05-11
EP0884327A1 (de) 1998-12-16
US6194543B1 (en) 2001-02-27
DE69704269T2 (de) 2001-11-22
DE69704269D1 (de) 2001-04-19

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